Intentional ablation of vestibular function using commercially available topical gentamicin-betamethasone eardrops in patients with Meniere's disease: further evidence for topical eardrop ototoxicity

OBJECTIVE: To determine whether the controversial findings of suspected ototoxicity from commercially available gentamicin sulfate and betamethasone sodium phosphate eardrops can be used in a therapeutic fashion to ablate (or attenuate) vestibular function in patients with unilateral Meniere's disease. STUDY DESIGN: Prospective case review. METHODS: At a tertiary care dizziness unit at the University Health Network, Toronto General Hospital, University of Toronto (Toronto, Ontario, Canada), adults with unilateral Meniere's disease undergoing intratympanic ablation therapy were studied. After insertion of a tympanostomy tube with the patient under local anesthesia, patients instilled gentamicin containing eardrops three times daily until they became vertiginous for longer than 24 hours and then for an additional 2 days longer or for 1 month, whichever came first. Electronystagmographic caloric test responses were measured before treatment using bithermal water caloric and after treatment using air caloric tests. Main outcome measures included clinical titration of drops to the onset of prolonged vertigo. As well, post-treatment findings on electronystagmography and audiometry were compared with pretreatment testing. RESULTS: Twenty patients were available for review. Fifteen patients had a significant reduction in caloric test responses compared with pretreatment values; among them, 10 patients had absent air caloric test responses on the treated side. In 10 patients hearing worsened according to the 1995 American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium Guidelines for reporting in Meniere's disease. CONCLUSIONS: Topical gentamicin-betamethasone eardrops can pass through a tube into the middle ear, where they may prove primarily vestibulo-ototoxic patients with Meniere's disease. The study further confirms clinical observations that gentamicin-containing eardrops might prove ototoxic, especially in noninflamed ears with a tympanic membrane defect.     

Ototoxicity of topical moxifloxacin in a chinchilla animal model

OBJECTIVE: Ciprofloxacin is currently the only proven nonototoxic topical antibiotic. However, its widespread use has resulted in the emergence of antimicrobial resistance. There are also concerns that there is currently no safe alternative to ciprofloxacin for patients with a nonintact eardrum. We thus wished to evaluate whether a moxifloxacin solution is ototoxic when used topically in chinchilla ears in the presence of a pressure-equalizing tube (PET). STUDY DESIGN: A prospective, randomized, controlled trial was conducted in an animal model. METHODS: Twenty chinchillas were included in this study. After bilateral insertion of PETs, four drops of a moxifloxacin solution were delivered twice daily for 7 days in the randomly assigned experimental ear. The control ear received an equal amount of a solution of Ringer's lactate. Distortion product otoacoustic emissions (DPOAE) were recorded at baseline (after PET insertion) and at days 1, 3, 7, 14, and 28 after treatment initiation. RESULTS: When baseline DPOAE measurements were compared with the final measurements at day 28, moxifloxacin caused a statistically significant (P < .05) hearing loss (HL) in the experimental ears for the frequencies between 3.7 and 15 kHz. There was no significant change in hearing in the control ears. CONCLUSION: This represents the first study on the ototoxicity of topical moxifloxacin. Our results demonstrate that moxifloxacin causes HL when used with a nonintact tympanic membrane in a chinchilla animal model.     

ototoxicity of styrene

Styrene is extensively used in industry,but its ototoxicity,in particular in the pregnant female and the offspring,is still not well understood.In the current study,young adult male rats and pregnant f...     

Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity

Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin’s ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.     

Ototoxicity of common topical antimycotic preparations

OBJECTIVE: To determine the ototoxic effects of five commonly used topical antimycotic agents-clotrimazole, miconazole, nystatin, tolnaftate, and gentian violet-in the guinea pig. DESIGN: A controlled animal study in which the ototoxicity of commonly used topical antifungal agents was investigated by measurement of hair cell loss. METHODS: Several readily available topical antimycotic preparations were instilled into the middle ears of female Hartley guinea pigs over a 1-week period. Two weeks after the last instillation, the animals were euthanized. An active control group was treated with neomycin to confirm the adequacy of the treatment in delivering a known ototoxin; an untreated control group defined the normal distribution of hair cells. The temporal bones were removed, and the cochleas were fixed and dissected. The basilar membranes were examined under the scanning electron microscope. A map of hair cell survival was made for each row in segments of each turn. RESULTS: The untreated control animals had no discernible hair cell loss in the two lower turns. In the apical turn and sometimes the third turn, loss of hair cells was a common finding, this is a known effect of aging in this species. The animals treated with neomycin had damage consistently in the basal turn, sometimes extending into the second turn, as well as the expected hair cell loss in the apical turn. Clotrimazole, miconazole, or tolnaftate did not cause any hair cell loss in the first two turns. Hair cell loss in the third and fourth turns was similar to that of the untreated control group. Likewise, nystatin exhibited no evidence of ototoxicity. Of note, however, the preparation used in this study left a persistent residue in the round window niche. Of the first four animals treated with gentian violet, three developed pronounced behavioral signs of vestibular damage, and three demonstrated extensive middle ear inflammation and extensive new bone growth. Hair cell counts were not attempted because the extreme bone growth interfered with successful perfusion and dissection. CONCLUSIONS: Extrapolating from guinea pigs to humans requires caution. However, it is likely that guinea pigs are, if anything, more susceptible to topical ototoxins than are humans. The specific antimycotics clotrimazole, miconazole, and tolnaftate appear to be safe. Gentian violet has the potential for severe damage. The persistent residue left by the nystatin preparation is cause for concern and is a reminder that both the active ingredient and vehicle must be considered in evaluation of safety.     

Using the Zebrafish Lateral Line to Screen for Ototoxicity

The zebrafish is a valuable model for studying hair cell development, structure, genetics, and behavior. Zebrafish and other aquatic vertebrates have hair cells on their body surface organized into a sensory system called the lateral line. These hair cells are highly accessible and easily visualized using fluorescent dyes. Morphological and functional similarities to mammalian hair cells of the inner ear make the zebrafish a powerful preparation for studying hair cell toxicity. The ototoxic potential of drugs has historically been uncovered by anecdotal reports that have led to more formal investigation. Currently, no standard screen for ototoxicity exists in drug development. Thus, for the vast majority of Food and Drug Association (FDA)-approved drugs, the ototoxic potential remains unknown. In this study, we used 5-day-old zebrafish larvae to screen a library of 1,040 FDA-approved drugs and bioactives (NINDS Custom Collection II) for ototoxic effects in hair cells of the lateral line. Hair cell nuclei were selectively labeled using a fluorescent vital dye. For the initial screen, fish were exposed to drugs from the library at a 100-muM concentration for 1 h in 96-well tissue culture plates. Hair cell viability was assessed in vivo using fluorescence microscopy. One thousand forty drugs were rapidly screened for ototoxic effects. Seven known ototoxic drugs included in the library, including neomycin and cisplatin, were positively identified using these methods, as proof of concept. Fourteen compounds without previously known ototoxicity were discovered to be selectively toxic to hair cells. Dose-response curves for all 21 ototoxic compounds were determined by quantifying hair cell survival as a function of drug concentration. Dose-response relationships in the mammalian inner ear for two of the compounds without known ototoxicity, pentamidine isethionate and propantheline bromide, were then examined using in vitro preparations of the adult mouse utricle. Significant dose-dependent hair cell loss in the mouse utricle was demonstrated for both compounds. This study represents an important step in validating the use of the zebrafish lateral line as a screening tool for the identification of potentially ototoxic drugs.     

Systemic Lipopolysaccharide Induces Cochlear Inflammation and Exacerbates the Synergistic Ototoxicity of Kanamycin and Furosemide

Aminoglycoside antibiotics are highly effective agents against gram-negative bacterial infections, but they cause adverse effects on hearing and balance dysfunction as a result of toxicity to hair cells of the cochlea and vestibular organs. While ototoxicity has been comprehensively studied, the contributions of the immune system, which controls the host response to infection, have not been studied in antibiotic ototoxicity. Recently, it has been shown that an inflammatory response is induced by hair cell injury. In this study, we found that lipopolysaccharide (LPS), an important component of bacterial endotoxin, when given in combination with kanamycin and furosemide, augmented the inflammatory response to hair cell injury and exacerbated hearing loss and hair cell injury. LPS injected into the peritoneum of experimental mice induced a brisk cochlear inflammatory response with recruitment of mononuclear phagocytes into the spiral ligament, even in the absence of ototoxic agents. While LPS alone did not affect hearing, animals that received LPS prior to ototoxic agents had worse hearing loss compared to those that did not receive LPS pretreatment. The poorer hearing outcome in LPS-treated mice did not correlate to changes in endocochlear potential. However, LPS-treated mice demonstrated an increased number of CCR2⁺ inflammatory monocytes in the inner ear when compared with mice treated with ototoxic agents alone. We conclude that LPS and its associated inflammatory response are harmful to the inner ear when coupled with ototoxic medications and that the immune system may contribute to the final hearing outcome in subjects treated with ototoxic agents.     

Protective Effect of Metformin Against Cisplatin-Induced Ototoxicity in an Auditory Cell Line

Metformin, an antidiabetic drug with potent anticancer activity, is known to prevent oxidative stress-induced cell death in several cell types through a mechanism dependent on the mitochondria. In the present study, we investigated the influence of metformin on cisplatin ototoxicity in an auditory cell line. Cell viability was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (Sigma, St. Louis, MO, USA) cell proliferation assay. Oxidative stress and apoptosis were assessed by flow cytometry analysis, Hoechst 33258 staining, reactive oxygen species (ROS) measurement, and western blotting. Intracellular calcium concentration changes were detected using calcium imaging. Pretreatment with 1 mM metformin prior to the application of 20 μM cisplatin significantly decreased the frequency of late apoptosis in HEI-OC1 cells and also significantly attenuated the cisplatin-induced increase in ROS. In addition, metformin inhibited the activation of caspase-3 and levels of poly-ADP-ribose polymerase (PARP). Pretreatment with metformin prevented the cisplatin-induced elevation in intracellular calcium concentrations. We propose that metformin protects against cisplatin-induced ototoxicity by inhibiting the increase in intracellular calcium levels, preventing apoptosis, and limiting ROS production.     

Ototoxicity and nephrotoxicity of gentamicin vs netilmicin in patients with serious infections. A randomized clinical trial

In the treatment of serious infection by aminoglycoside antibiotics multiple daily treatment with netilmicin is considered to be the least toxic. Studies comparing netilmicin with gentamicin using the less toxic once-daily schedule are lacking. A randomized prospective study was designed to evaluate the efficacy and toxicity of once-daily netilmicin with gentamicin treatment in patients with serious infections. Consecutive patients with serious infections were randomized between gentamicin 4 mg/kg q24h iv or netilmicin 5.5 mg/kg q24h iv. Exclusion criteria were neutropenia or severe renal failure. A good clinical response was observed in 50 of the 54 evaluable patients (92.6%) treated with gentamicin and in 48/52 (92.3%) netilmicin treated patients. Nephrotoxicity developed in 5/72 (6.9%) gentamicin patients and in 10/69 (14.5%) treated with netilmicin. Audiometry was performed with high-frequency audiometry when possible; no significant differences were found between the two aminoglycosides. We conclude that with once-daily treatment no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated.     

Tetracaine topical anesthesia for myringotomy

OBJECTIVES/HYPOTHESIS: To study the efficacy and safety of topical tetracaine anesthesia for office myringotomy and myringotomy with a tube. STUDY DESIGN: Retrospective review of patients undergoing office myringotomy, with or without tube insertion, performed over a 4-year period. METHODS: A topical solution of 8% tetracaine base in 70% isopropyl alcohol was used in 381 ears. Five to 10 drops of the solution were applied to the tympanic membrane for 10 to 15 minutes and aspirated. Myringotomy was performed either with a myringotomy knife or with a CO(2) laser (OtoLAM). RESULTS: Topical tetracaine was used in all 231 ears (100%) undergoing myringotomy without a tube and 150 of 212 ears (71%) undergoing myringotomy with a tube. Tetracaine alone was effective in providing tympanic membrane anesthesia in 95% of myringotomy without a tube (220 ears) and in 93% of myringotomy with a tube (139 ears). There were six complications, including five cases of severe vertigo and one unusual prolonged, transient facial nerve weakness. CONCLUSION: Topical tetracaine is efficacious and safe for use in office myringotomy.     

Ototoxicity of kanamycin in developing rats: Relationship with the onset of the auditory function

In order to test the relationship between the ototoxicity of kanamycin and the onset of the auditory function, two groups of developing rats were intoxicated with kanamycin before and after the period of onset of cochlear potentials (8th postnatal day). Kanamycin was shown to have a weak ototoxic effect before the 8th postnatal day and a strong ototoxic effect after this period. These results indicate a critical period of sensitivity to ototoxic antibiotics during auditory development.     

Intraotic Administration of Gentamicin: A New Method to Study Ototoxicity in the Crista Ampullaris of the Bullfrog

A new method of local gentamicin administration was tested in the bullfrog inner ear to achieve ototoxic-induced hair cell destruction. Gelfoam pledgets soaked with known amounts of gentamicin were inserted into the perilymphatic cisterna of the bullfrog through a ventral surgical approach. A dose of 1.20 mg gentamicin, consistent with a perilymphatic concentration of 65 μg/ml, resulted in the desired ototoxic-induced hair cell damage, that is, complete hair cell destruction with minimal disruption of other components of the sensory epithelium. This study demonstrates that this is a useful and simple method to investigate the process of vestibular ototoxicity and hair cell regeneration, including aspects of hair cell destruction and repair.     

Inner ear changes with intracochlear gentamicin administration in Guinea pigs

OBJECTIVES/HYPOTHESIS: Transtympanic administration of gentamicin is reported to be a useful treatment for vertigo in such conditions as Meniere's disease, and determining appropriate clinical dosage of gentamicin is difficult. The authors examined the relation between gentamicin dosages and inner ear function in guinea pigs. STUDY DESIGN: This study is a basic science project designed to examine cochlear and vestibular function in animal models. METHODS: Various concentrations of gentamicin solution were infused into the right inner ear of guinea pigs by osmotic pumps. Caloric nystagmus as a marker of vestibular function and the change in auditory brainstem response (ABR) threshold as a marker of cochlear function were observed. RESULTS: After 14 days of treatment, high gentamicin concentrations of 40 mg/mL caused canal paralysis and a rapid shift in ABR threshold. Animals exposed to low gentamicin concentrations of 4 mg/mL showed no obvious change in either vestibular or cochlear function. Animals exposed to moderate gentamicin concentrations of 12 mg/mL showed a moderate shift in ABR threshold and caloric malfunction. Histopathological examination revealed that after 14 days of treatment with 40 mg/mL gentamicin, severe cytoplasmic damage occurred in both vestibular and cochlear end organs. In animals treated with 12 mg/mL gentamicin, hair cells remained in the cochlear third turn and ampulla of the lateral semicircular canal. CONCLUSION: The authors established an animal model that showed the moderate damage of inner ear with moderate-dose gentamicin. The study results indicated that the appropriate administration of gentamicin could establish a stable effect on the inner ear. It may be important to select the protocol that delivers a stable dosage of gentamicin to treat patients with Meniere's disease safely and effectively.     

Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity

Gentamicin is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Treatment with this antibiotic carries the potential for adverse side effects, including ototoxicity and nephrotoxicity. Ototoxic effects are at least in part a consequence of oxidative stress, and various antioxidants have been used to attenuate gentamicin-induced hair cell death and hearing loss. Here, a combination of nutrients previously shown to reduce oxidative stress in the hair cells and attenuate hearing loss after other insults was evaluated for potential protection against gentamicin-induced ototoxicity. Guinea pigs were maintained on a nutritionally complete standard laboratory animal diet or a diet supplemented with β-carotene, vitamins C and E, and magnesium. Three diets with iterative increases in nutrient levels were screened; the final diet selected for study use was one that produced statistically reliable increases in plasma levels of vitamins C and E and magnesium. In two separate studies, significant decreases in gentamicin-induced hearing loss at frequencies including 12 kHz and below were observed, with less benefit at the higher frequencies. Consistent with the functional protection, robust protection of both the inner and outer hair cell populations was observed, with protection largely in the upper half of the cochlea. Protection was independently assessed in two different laboratories, using two different strains of guinea pigs. Additional in vitro tests did not reveal any decrease in antimicrobial activity with nutrient additives. Currently, there are no FDA-approved treatments for the prevention of gentamicin-induced ototoxicity. The current data provide a rationale for continued investigations regarding translation to human patients.     

Comparative antibacterial activity of topical antiseptic eardrops against methicillin-resistant Staphylococcus aureus and quinolone-resistant Pseudomonas aeruginosa

ObjectiveAural irrigation using antiseptic solutions can be an effective medical treatment of chronic suppurative otitis media (CSOM) owing to the increasing prevalence of antibiotic-resistant CSOM infections. In the present study, we compared the antimicrobial activities of 100% Burow's solution, 50% Burow's solution, 2% acetic acid, vinegar with water (1:1), and 4% boric acid solution against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), quinolone-resistant Pseudomonas aeruginosa (QRPA), and quinolone-susceptible P. aeruginosa (QSPA) in vitro.MethodsWe examined the antimicrobial activities of five antiseptic solutions against MRSA, MSSA, QRPA, and QSPA. The antimicrobial activities of the solutions were calculated as a percentage of the surviving microorganisms by dividing the viable count in each antiseptic solution with that in control. The time (D₁₀ value) required for each of the five solutions to inactivate 90% of the microorganism population was also investigated.ResultsBurow's solution exhibited the highest antimicrobial activity and the lowest D₁₀ value against MRSA, MSSA, QRPA, and QSPA, followed by 2% acetic acid, vinegar with water (1:1), and 4% boric acid solution.ConclusionOur results indicate that Burow's solution has the most potent activity against bacteria including antibiotic-resistant strains. Twofold dilution of the solution is recommended to avoid ototoxicity.     

Ototoxicity caused by topical administration of gentamicin versus tobramycin in rabbits

Aim

To investigate the possible differences in cochleotoxic effects in rabbits between twice-daily administration of topical gentamicin and tobramycin throughout the perforated tympanic membrane with the use of distortion-product otoacoustic emissions (DPOAEs).

Materials and methods

Twenty female rabbits were studied prospectively daily for 21 days. The rabbits’ ears were divided into two groups: right and left ear groups. Twice-daily for 21 days after paracentesis, 0.3% gentamicin was administered topically in the left ears, and 0.3% tobramycin was administered topically in the right ears. For 21 days, the cochlear activity of the right and left ears of all rabbits was examined every 7 days using DPOAEs. The numerical values of the distortion product (DP) intensity recorded on days 7, 14 and 21 of drug administration were compared between the two groups.

Results

Cochlear activity was reduced earlier in the gentamicin group in the 2-4 kHz frequencies compared to the tobramycin group in the second DPOAE measurement (day 7 of the experiment). In two rabbits in the gentamicin group, the third DPOAE measurement showed that cochlear activity was reduced in all frequencies. In six rabbits in the tobramycin group, the third DPOAE measurement showed that cochlear activity was reduced in all frequencies. There was no statistical significance between the two groups except day 7 in the 2 and 3 kHz frequencies (p < 0.05).

Conclusion

We concluded that low frequencies (2 and 3 kHz) are more sensitive to the administration of topical gentamicin than to topical tobramycin. Early cessation of tobramycin drops may be minimally cochlear toxic compared to gentamicin within the first 7 days when these drugs are misused in treating chronic otitis media.